*3.2.1 Cellular and molecular processes in neuropsychiatric systemic lupus erythematosus (NPSLE)*

Overactive adaptive immune cells, autoantibody generation, immunological complex accumulation, and multisystem damage are features common in SLE, an

#### *Lupus and the Nervous System: A Neuroimmunoloigcal Update on Pathogenesis and Management… DOI: http://dx.doi.org/10.5772/intechopen.107970*

early autoimmune disorder with a strong hereditary component. As previously stated, different elements could play a role in the development of SLE. Mutations in immunity-related genes, such as C1q, C1r, C1s, C2, or C4, which are essential elements of the complement cascade, are one of these reasons. These supplements play a role in the detection and opsonization of apoptotic cells, as well as the clearance of critical immune complexes, and their absence can result in the creation of autoantigens, as well as the stimulation of interferon (IFN) types 1 and 2 [42, 43].

Other mutations in genes that regulate nucleic acid metabolism, including TREX1, RNASEH2B (A, C), ADAR, IFIH1, and SAMHD1, trigger SLE-like symptoms that are mediated by a type I chronic response to IFN. Alleles associated with the B cell response (BLK, BANK1, FCGR2A, and PTPN22) as well as alleles associated with the innate immunological response (IRF5, STAT4, TNFAIP3, and TNFSF4) are also associated with SLE [44, 45].

In SLE, epigenetic modifications include DNA methylation, histone modifications, and noncoding transcripts. DNA methylation suppressors can induce T cell reactivity and lupus symptoms in mice and humans. In addition, T cells from patients with SLE have less methylation than T cells from healthy individuals. Studies of single-site methylation reveal that SLE patients had unique mutations in the PRF1, TNFSF7 (CD70), ITGAL, and CD40LG genes, among others [46, 47]. SLE pathogenesis is associated with aberrant histone acetylation, which is associated with higher histone H3 and H4 acetylation in human CD4 SLE T cells [48]. In SLE patients, the expression of miR-126-3p, miR-let7d-5p, miR-15a-5p, miR-326, miR98-5p, miR143-3p, miR-7, miR 21, and miR22 increased, whereas miR-31 and miR-146a, the negative regulator of IFN type I signaling, decreased. Negative regulators of IFN type I signaling, miR-31 and miR-146a, were decreased in SLE patients. In SLE B cells, miR-7, miR-21, and miR-22 levels were all elevated relative to the control group, and all three miRs suppressed PTEN expression. Reduced PTEN expression in SLE B cells correlates with B cell hyperactivity and the potential failure of B cell tolerance, suggesting that this microRNA may play a role in the etiology of SLE. Let 7 levels were seen to fluctuate in lupus nephritis samples, suggesting that it suppresses NFkB signaling. SLE patients and lupus nephritis tissue samples exhibit increased NFkB signaling in B cells. Reduced miR-31 expression is associated with lower IL-2 expression in SLE patients, indicating that miR-31 plays a mechanical role in the disease [49–51].

#### *3.2.2 NR2A/B antibodies of anti-N-methyl-d-aspartate (NMDA) receptor subunit*

Neurons contain the glutamate receptor and ion channel NMDA. 30–40% of SLE patients' sera include antibodies against the NR2A/B subunit of the NMDA receptor. After establishing evidence of R4A antibody (as anti-dsDNA antibody) interaction with NRDA NR2A and NR2B receptor subunits, researchers sought similar antigenic characteristics in polyclonal anti-dsDNA antibodies in SLE patients. Anti-NR2A/B antibodies induce apoptotic cell death in cell culture, according to prior investigations. Anti-NR2A/B antibodies were injected into the hippocampus of C57BL/6 mice, causing neuronal death. In addition, intravenous administration of anti-NR2A/B antibodies to BALB/c mice treated with LPS resulted in antibody binding to hippocampal neurons and nerve damage [52, 53].

#### *3.2.3 Matrix metalloproteinases (MMPs)*

MMPs are a class of zinc- and calcium-dependent endoproteinases involved in the degradation and regeneration of extracellular matrix proteins. MMPs, especially MMP-9, are able to degrade basal layer components such as collagen type IV, fibronectin, and laminin, as well as aid in proteolyzing the basal layer, resulting in BBB disruption. Numerous immune-type cells (granulocytes, lymphocytes, and monocytes) release MMP-9, with neutrophils being one of the most prolific sources. Serum and CSF levels of MMP-9 in SLE patients with CNS involvement are elevated, according to the available evidence. MMP-9 levels in the CSF are also associated with tau protein and glial fibrillar acid, markers of neurodegeneration and astrocytic degeneration, respectively, in SLE patients [54, 55].

#### *3.2.4 Neutrophil extracellular traps (NETs)*

Neutrophils are guardians of the innate immune system that migrate from the bloodstream to infection sites to combat pathogens by phagocytosis, degranulation, and the release of neutrophil extracellular traps (NETs). Neutrophil extracellular vesicles (NETs), which are produced by active neutrophils, are a distinct kind of cell death from necrosis and apoptosis. NETs with fibrous structures contain histones (H1, H2A, H2B, H3, and H4) and granule-derived enzymes, including neutrophil elastase, myeloperoxidase, and MMP-9. Antibacterial characteristics exist within histones. In addition to elevated reactive oxygen species (ROS) in neutrophils, transmission across activated endothelium in vivo stabilizes NET formation and may result in cell death. Neutrophils in SLE patients have altered functional characteristics due to the overexpression of granulopoiesis-related genes, such as decreased phagocytic capabilities, increased intravascular activation, increased platelet-neutrophil accumulation, and increased production of reactive oxygen species [56, 57].

#### *3.2.5 Pro-inflammatory mediators*

In the hippocampus of animal models with NPSLE, infiltration of CD3+ T cells and enhanced mRNA expression of proinflammatory mediators including IL-1, IL-6, IL-10, interferon (IFN)- and transforming growth factor were observed. In the CNS, cytokines are produced by neurons and microglia. Studies have indicated that neurons and microglial cells are capable of synthesizing IL-2, IL-6, IL-8, and IL10 intrathecally. Levels of IL-6 in the cerebrospinal fluid (CSF) were associated with abnormal brain MRI signals in human NPSLE, which were predominantly white matter intensities weighted with T2. In 119 SLE patients, IL-6 CSF levels were related to MMP-9 CSF levels, suggesting that BBB failure may be involved in the development of brain MRI abnormalities in patients with NPSLE [58, 59].

#### **3.3 Diagnosis**

NPSLE is challenging to treat in clinical practice due to the variety of clinical presentations, the shortage of pathology specimens to diagnose the underlying etiology, and the paucity of evidence-based therapies [60]. Before making a definitive diagnosis of NPSLE, professionals must rule out other probable causes, such as infections and cancers, due to the disease's difficulty to identify [32, 61]. Neuropsychiatric manifestations of SLE comprise a broad spectrum of symptoms that impair patient prognosis and quality of life. Recent advances have been achieved in both improving the diagnosis of NPSLE and elucidating its etiology. For the diagnosis of NPSLE, there is no gold standard [62]. In all patients with unexplained neuropsychiatric symptoms or presentations indicative of neuropsychiatric (NP) disease, the first step

#### *Lupus and the Nervous System: A Neuroimmunoloigcal Update on Pathogenesis and Management… DOI: http://dx.doi.org/10.5772/intechopen.107970*

would be to investigate and characterize the NP symptoms while ruling out other common causes, such as infections, metabolic disorders, or drug use. Thrombotic events, atherosclerotic disease, cardiovascular risk factors, and general SLE activity are evaluated in greater detail [61]. Different clinical, serological, immunological, electrophysiological, and neuroimaging tests are utilized to diagnose NPSLE. Various imaging modalities and the presence of autoantibodies can aid in diagnosing the cause and the optimal treatment protocol [63]. Neuroimaging can be used to differentiate SLE patients from healthy controls, but further research is required to differentiate among lupus patients with and without neuropsychiatric symptoms. As potential markers for a more objective and accurate diagnosis, higher levels of certain substances in the cerebrospinal fluid and serum, as well as the presence of particular autoantibodies, have been detected [20, 64].

To accurately classify NP, imitators must be excluded with care. However, NP episodes must be associated with SLE in order to receive immunosuppressive therapy. To improve clinical care and research outcomes, a number of attribution models have been developed [65, 66]. Numerous practitioners now employ the well-established language of the American College of Rheumatology (ACR) to define NPSLE episodes in clinical practice [18]. Most commonly utilized are the ACR criteria from 1999, which have been validated in an external cohort with a sensitivity and specificity of 45% [67]. The ACR criteria must be amended and updated, including the addition of new manifestations, notwithstanding the considerable progress made since their release (e.g., posterior reversible encephalopathy syndrome, small fiber neuropathy, and chronic inflammatory progressive demyelination). Various classification criteria have been developed over time [18, 68–71]. Another criterion devised an attribution method that produces a probability value between 0 and 10. This algorithm evaluates four subjects during model construction, three of which are identical to those used in ACR standards. In this context, issues discussed include the existence of mild or common neuropsychiatric episodes as well as EULAR-suggested SLE risk factors [72]. As the ACR criteria displayed a high sensitivity (91%) but a low specificity (46%), Zhang et al. presented their own criteria based on five symptoms (disease activity, antibodies, thrombosis, skin lesions, and manifestations) whose positive and negative prognostic values were greater than 70% [17].

SLE patients could be evaluated for cognitive impairment, anxiety, and depression using a number of screening procedures established for neurodegenerative illnesses. ACR's ad hoc interdisciplinary committee recommended specific neuropsychological tests (NPTs) for identifying cognitive dysfunction (CD) in SLE [18]. Even for limited inspections, NPTs are time-consuming, costly, and inaccessible in a variety of situations. The Automated Neuropsychologic Assessment Metrics (ANAM), a computerized method, measures many of the same cognitive categories as the Neuropsychological Tests (NPTs) [73]. NPT and ANAM are time-consuming, somewhat costly, and difficult to obtain; hence, a simple and sensitive screening test is necessary for clinical therapy [74]. According to preliminary studies, the Montreal Cognitive Assessment Questionnaire (MoCA) is a brief and affordable screening tool that may be useful for the early detection of CD in SLE [75, 76]. In comparison to normal individuals or patients with rheumatoid arthritis, the MoCA demonstrated moderate sensitivity and specificity for cognitive impairments (0.83–0.94 and 0.27–0.46, respectively) [77]. Other cognitive decline screening instruments, such as the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE), have been utilized in the elderly. The IQCODE is a questionnaire that is completed by the patient's family or an appropriate informant who knows the patient well and can

determine if the patient's cognitive function has decreased in relation to regular daily activities over time. The IQCODE is not affected by the patient's educational level, premorbid IQ, or proficiency in the culture's predominant language, but it can be influenced by the quality of the informant-patient relationship [78].

Self-informed surveys, for example, the hospital anxiety and depression scale (HADS), the Center for Epidemiologic Studies-Depression Scale (CES-D), and beck anxiety inventory (BAI) are low-cost and widely used screening utilities for depression and anxiety in the general inhabitants; however, only a handful of researches have inspected their function in SLE patients [79, 80]. Previously reported in a crosssectional study of 159 consecutive consenting SLE adults to determine the reliability of assessment in these questionnaires' test-retest, prevalence of depression and anxiety in SLE patients, and study their diagnostic correctness (HADS-A), the prevalence of anxiety ranged from 45% (BAI) to 50% (CES-D) (CES-D) and the prevalence of depression ranged from 29% (HADS-D) to 52% (CES-D). According to the authors' conclusion, both surveys have the potential to serve as NPSLE screening tools [74].

None of the laboratory or neuroimaging biomarkers for diagnosing NPSLE have been proven accurate or reliable in clinical practice, despite extensive clinical research. Novel biomarkers may permit a more objective evaluation [81]. It might be as easy as measuring the concentration of a certain biomarker in the blood. Autoantibodies, the defining characteristic of lupus, may be useful as biomarkers. Numerous autoantibodies have been linked to NPSLE, but their role in pathogenesis remains unproven [82]. One of the potential biomarkers is 2-glycoprotein 1 and cardiolipin, which have been associated with focal neuropsychiatric diseases including cerebrovascular disease, seizures, and chorea, as well as diffuse neuropsychiatric disorders like cognitive impairment, psychosis, sadness, and headache [83, 84]. Ribosomal P protein, which is associated with NPSLE by demonstrating greater titers during active SLE in serum and CSF, is not a helpful biomarker for discriminating between disease subtypes [85–87]. Antibodies against NR2, a subunit of the N-methyl D-aspartate receptor (NMDAR), are associated with spatial memory impairment in both mice and lupus patients. NR2 is essential for synaptic plasticity and memory in the brain [81, 88–93]. Using primary brain micro-vessel endothelial cells, it was demonstrated that anti-NR2 antibodies can breach the BBB and enter the brain [94]. Several additional biomarkers, such as Microtubule-associated protein 2, were indicated to have a connection with NPSLE that was either significant or contentious (MAP-2) [95], U1 ribonucleoprotein (U1RNP) [96], and Glial fibrillary acidic protein (GFAP) [88, 97]. Although autoantibodies have been suggested as a potential biomarker, only a few antibodies, such as antineuronal, anti-ribosomal P, and anti-NR2 antibodies, have met the exploratory criteria and are being utilized in diagnosis and therapeutic decisions [98, 99].

In addition, numerous neuroimaging techniques, such as nuclear medicine techniques and magnetic resonance imaging (MRI), have enabled the assessment of functional and structural irregularities in SLE patients, thereby facilitating a greater comprehension of the underlying pathophysiology and subsequent pathophysiological alterations [6]. Since the 1980s, aberrant brain MRI has been described in SLE and NP-SLE [100, 101]. On conventional MRI (cMRI), a significant proportion of patients with NP-SLE show no abnormalities, and global markers such as lesion load or brain atrophy do not correlate with symptom severity [102, 103]. Innovative MRI techniques and software may be more precise in identifying brain variations in NPSLE patients. Researchers were able to map the microstructure of the brain utilizing mean diffusivity and fractional anisotropy (DTI), sophisticated MRI methods including

white matter hypersensitivity volumetry, diffusion-tensor imaging (DTI), and voxelbased morphometry (VBM) [104]. However, there is yet a radiological and clinical contradiction. To eliminate this uncertainty, a broad strategy and imaging surveys are required.

#### **3.4 Management and treatment**

The management of NPSLE could be challenging at multiple phases, including problems in classifying them as SLE, diagnosis based on ambiguous symptoms, and the limited and imprecise arsenal of available therapies. Initially, a thorough evaluation should be conducted to rule out alternative reasons, such as metabolic diseases, infection, cancer, and severe drug reactions. Once the symptoms are mostly attributed to SLE and these confounding variables have been ruled out, the management goals are increased. First, symptomatic medication should be administered, including antiepileptics for seizures, treatment of hypertension and metabolic abnormalities, and mood stabilizers, anxiolytics, antidepressants, or antipsychotics, as indicated, for psychiatric symptoms. Until then, therapy of the underlying SLE process should be administered in accordance with whether the neuropsychiatric manifestations are attributable to a widespread, inflammation-driven condition or a process [61]. Before further actions, it is necessary to consider the challenges associated with NPSLE management.

First, concerns unrelated to SLE should be addressed appropriately with non-SLE-related therapies. A study described the beneficial effects of psychotherapy on reducing sadness and anxiety and boosting life satisfaction [105]. Anxiolytics and antidepressants are also used to improve cognitive skills in SLE patients with anxiety and depression; however, their use in mood disorders is inconsistent [106]. Effective antiepileptics and antipsychotics are used to treat SLE psychosis and seizures, respectively [107, 108]. The cognitive dysfunction caused by SLE is managed to utilize a technique known as meta-context behavioral rehabilitation. A nonrandomized study of rehabilitation strategies revealed a 100 percent retention rate with memory selfefficacy and an improvement in quality of life [109]. This emphasizes the relevance of non-SLE concerns in the quality of life of patients. In addition, non-SLE therapies offer the potential for ameliorating these problems. To unravel the pharmacological components of this strategy, a controlled trial should be conducted.

In the absence of controlled clinical trials, certain NPSLE therapies are experimental. Depending on the underlying pathophysiology, pharmaceutical therapy in the clinical environment is aimed at reducing inflammation or preventing thrombotic events [110]. In patients with immune-mediated damage or global lupus, immunosuppressants such as corticosteroids must be provided alone, or in combination with additional immunosuppressive medications such as azathioprine, mycophenolate mofetil, and cyclophosphamide. Immunotherapy's primary objective is to treat or relieve symptoms [61]. Only oral prednisolone and intravenous cyclophosphamide have demonstrated efficacy in the treatment of NPSLE [111]. Seizures are less likely to occur in people receiving antimalarials [108]. Other co-administered medications include statins for patients with arterial or recurrent venous thromboembolism, as well as nonsteroidal anti-inflammatory medicines (NSAID) for pain management [112]. Nonetheless, the use of NSAIDs in SLE is associated with an increased likelihood of recurrent aseptic meningitis. Anticoagulants and antiplatelet treatments are used to treat ischemic NPSLE, especially in patients with positive antiphospholipid (aPL) antibodies. Typically, inflammatory and ischemic NPSLE coexist; we advise a combination of antiplatelet treatment, anticoagulation, and immunosuppressive

drugs [20]. All thromboses caused by aPL-antibody require lifelong anticoagulation with warfarin as the primary treatment [113]. Since the safety profile of antimalarials and statins is promising, they should be evaluated as alternatives to warfarin, particularly in patients with persistent thrombosis. In addition, low-dose aspirin is recommended for people with cardiovascular risk factors. Although randomized clinical trials are now underway, the available data are insufficient to recommend direct oral anticoagulants (as well as novel oral anticoagulants) to prevent aPL-antibody-mediated thromboembolic events. It is recommended to administer intravenous immunoglobulin infusions, pulse corticosteroids, and/or plasmapheresis to patients with NPSLE and severe anti-phospholipid syndrome (APS). Numerous small series and case reports found that the use of eculizumab into these treatments was beneficial [114]. There is a vast variety of pharmacotherapies for NPSLE, each of which requires careful evaluation, illustrating the sensitivity of treatment selection for this disease.

In addition, six months of oral cyclophosphamide therapy followed by azathioprine maintenance medication was successful in treating lupus psychosis. The addition of Rituximab (or a different anti-CD20 monoclonal antibody) to the NPSLE therapy procedure requires consideration, notwithstanding the unreliability of the data supporting this practice. The efficacy of Rituximab was evaluated in ten patients with persistent NPSLE who saw rapid and considerable improvement in clinical symptoms and signs, consistent with radiological findings [115]. In a retrospective study of pediatric patients with NPSLE, Rituximab was also effective and largely safe [116]. These results demonstrate that the CD20 receptor plays a critical role in the pathogenesis of NPSLE, consistent with the immune cells that express this receptor, highlighting the importance of immune system-induced inflammation in this disease.
